The field of cancer stem cells (CSCs) is a rapidly emerging and exciting new area of oncology. CSCs are malignant stem cells that originate and grow tumors. These cells comprise a small portion (about 0.5%-2%) of a tumor, yet are responsible for the growth of the entire tumor. Importantly, CSCs are resistant to standard and targeted chemotherapy, and are believed to contribute to treatment failure and relapse. It is widely anticipated that new compounds designed to target CSCs will become the next generation of oncology drugs, with the potential to provide durable, relapse-free responses. Emphasizing the importance of CSCs, the NCI recently stated that the Institute "has identified cancer stem cells as 1 of the most important new ideas in cancer research..." (Boston Globe, 12/26/2004). There are 10,500 new cases of AML annually, and 70% of patients experience relapse after first- line therapy. The resistance of leukemia CSCs to standard chemotherapy is likely a major contributor to this treatment failure. Stemline Therapeutics' lead drug, named "SL-101", is designed to target and eradicate leukemia CSCs. Importantly, leukemia CSCs express more than 10-fold higher levels of CD123 (IL3Ra chain) than normal hematopoietic cells, making CD123 an ideal target for therapy. SL-101 is a chimeric immunotoxin consisting of the CD123-binding domain of a monoclonal antibody connected to a Pseudomonas exotoxin, and is in development in collaboration with the National Cancer Institute. SL-101 is designed to address the urgent need for leukemia therapies that provide durable remissions. Stemline has exclusively licensed intellectual property that protects SL-101. This Phase I STTR grant will cover the development of SL-101 through key phases of pre-clinical development. In particular, this study aims to develop SL-101 through in vitro assays and in vivo models of human acute leukemia in collaboration with Dr. Malcolm Moore at the Memorial Sloan-Kettering Cancer Center (New York, NY). SL-101 will be tested against leukemia cell lines and primary human leukemia and leukemia CSC samples, and in xenograft models of human acute leukemia, for its efficacy as an anti- leukemia agent. The SL-101 development plan is designed to advance SL-101 through animal efficacy at which time the Company expects to apply for a Phase II STTR to fund further pre-IND work including the required toxicology, manufacturing, and scale-up to support IND filing in preparation for Phase I/II clinical trials. There are 10,500 new cases of AML annually, and 70% of patients experience relapse after first- line therapy. The resistance of leukemia cancer stem cells to standard chemotherapy is the major contributor to this treatment failure and relapse. Stemline Therapeutics' lead drug, named "SL-101", is designed to target and eradicate leukemia cancer stem cells. SL-101 is designed to address the urgent need for leukemia therapies that provide durable remissions. This Phase I STTR grant will cover the development of SL-101 through key phases of pre-clinical development. [unreadable] [unreadable] [unreadable]